The invention relates generally to the use of recombinant viruses to deliver a desired transgene to retinal pigment epithelial cells of patients suffering from retinal degenerative diseases.
The relationship between the neurosensory photoreceptors and the adjacent retinal pigment epithelium (RPE) controls not only normal retinal function, but also the pathogenesis of hereditary retinal degenerations. Recent progress has identified the molecular bases for primary photoreceptor diseases, such as retinitis pigmentosa (Dryja, T. P., et al. 1990 Nature 343, 364-366; Farrar, G. J., et al. 1991 Nature 354, 478-480; and McLaughlin, M. E. et al, 1993 Nature Genetics 4, 130-134). Similarly the molecular bases for RPE diseases that cause photoreceptor blindness, such as child-onset severe retinal dystrophy, Leber's congenital amaurosis, and Best macular dystrophy, have been identified (Gu, S.-M., et al. 1997 Nature Genetics 17, 194-197; Marlhens, F., et al. 1997 Nature Genetics 17, 139-141; Petrukin, K., et al. 1998 Nature Genet 19, 241-247; and D'Cruz, P., et al. 2000 Hum. Mol. Genet. 9, 645-651). Despite these reported scientific advances, effective therapy for human retinal degenerations is still lacking.
Retinal gene therapy has been considered a possible therapeutic option for man. For example, U.S. Pat. No. 5,827,702 refers to methods for generating a genetically engineered ocular cell by contacting the cell with an exogenous nucleic acid under conditions in which the exogenous nucleic acid is taken up by the cell for expression. The exogenous nucleic acid is described as a retrovirus, an adenovirus, an adeno-associated virus or a plasmid. See, also, International Patent Publication Nos. WO 00/15822, published Mar. 23, 2000 and WO 98/48097, published Oct. 29, 1998.
A review of gene therapy efforts to date indicates that such efforts have focused mainly on slowing down retinal degeneration in rodent models of primary photoreceptor diseases. Normal genes and mutation-specific ribozymes delivered to photoreceptors have prolonged the lifetime of these cells otherwise doomed for apoptotic cell death (Bennett, J., et al. 1996 Nat. Med. 2, 649-654; Bennett, J., et al. 1998 Gene Therapy 5, 1156-1164; Kumar-Singh, R. & Farber, D., 1998 Hum. Mol. Genet. 7, 1893-900; Lewin, A. S., et al. 1998 Nat. Med. 4, 967-971; Ali, R., et al. 2000 Nat. Genet. 25, 306-310; Takahashi, M. et al, 1999 J. Virol. 73, 7812-6; Lau, D., et al. 2000 Invest. Ophthalmol. Vis. Sci. 41, 3622-3633; and LaVail, M. M., et al. 2000 Proc Natl Acad Sci USA 97, 11488-11493).
Retinal gene transfer of a reporter gene, green fluorescent protein, using a recombinant adeno-associated virus was demonstrated in normal primates (Bennett, J., et al. 1999 Proc. Natl. Acad. Sci. USA 96, 9920-9925). However, an as-yet unmet goal of research is the restoration of vision in a blinding disease of animals, particularly humans and other mammals, caused by genetic defects in RPE and/or photoreceptor cells.
There remains a need in the art for methods for effectively treating humans and other mammals or other animals suffering from blindness due to genetic defects or deficiencies, so as to restore sufficient vision to enable the subject to function in response to visual cues.